The charge-dipole pocket: a defining feature of signaling pathway GTPase on/off switches.
The charge-dipole pocket: a defining feature of signaling pathway GTPase on/off switches.
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DOI：
10.1016/j.jmb.2009.05.001
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发表时间：
2009-07-03
影响因子：
5.6
通讯作者：
Neuwald, Andrew F.
中科院分区：
文献类型：
--
作者：
Neuwald, Andrew F.
Ras 样 GTP 酶在细胞内信号通路中充当开关。它们的开启或关闭状态是通过所谓的开关 I 和 II 区域的构象变化来传达的。人们普遍认为这些 GTP 酶的独特分子特征是众所周知的。然而，在这里，我通过对 GTP 酶进化分歧的贝叶斯迭代分析，确定了一个先前未描述的开关 II 结构组件（以及先前描述的功能关键残基），它最能区分这些信号通路开关与其他 GTP 酶。在某些 Ras 样 GTP 酶中，这种新鉴定的组分在开关 II 螺旋末端的负偶极矩周围形成芳香口袋，并在口袋中插入带正电的残基。该螺旋以远离 GTPase 核心的特定方向定向，但在电荷偶极口袋破坏时会急剧重新定向。电荷偶极子袋发生在开状态和关状态下，并且电荷偶极子袋和替代配置都发生在关状态下的 Rab5a GTPase 单晶结构的晶胞内。因此，电荷偶极口袋构型与开或关状态无关，而是与外向螺旋的形成密切相关，因此与开关 II N 端区域的重组密切相关，该区域在感知开关状态以及介导 GTP 水解和核苷酸交换方面发挥着关键作用。
Ras-like GTPases function as on-off switches in intracellular signaling pathways. Their on- or off-state is communicated through conformational changes in the so-called switch I and II regions. It is commonly believed that the distinguishing molecular features of these GTPases are well known. Here, however, I identify—through a Bayesian iterative analysis of GTPase evolutionary divergence—a previously undescribed switch II structural component that (along with previously described, functionally critical residues) most distinguish these signaling pathway on-off switches from other GTPases. In certain Ras-like GTPases this newly-identified component forms an aromatic pocket around the negative-dipole moment at the end of a switch II helix with a positively-charged residue inserted into the pocket. This helix is oriented in a specific direction away from the GTPase core, but is dramatically reoriented upon disruption of the charge-dipole pocket. The charge-dipole pocket occurs in both the on- and off-states and both the charge-dipole pocket and an alternative configuration occur within the unit cell of a single crystal structure of Rab5a GTPase in the off-state. Thus, the charge-dipole pocket configuration is closely associated, not with the on- or off-state, but rather with formation of the outward-oriented helix and, as a result, with restructuring of the switch II N-terminal region, which plays a critical role both in sensing the on-off state and in mediating GTP hydrolysis and nucleotide exchange.
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